Conjunctival melanoma copy number alterations and correlation with mutation status, tumor features, and clinical outcome

Kenawy, Nihal; Kalirai, Helen; Sacco, Joseph J.; Lake, Sarah L.; Heegaard, Steffen; Larsen, Ann‐Cathrine; Finger, Paul T.; Milman, Tatyana; Chin, Kimberly J.; Mosci, Carlo; Lanza, Francesco; Moulin, Alexandre; Schmitt, Caroline A.; Caujolle, Jean‐Pierre; Maschi, C.; Marinković, Marina; Taktak, Azzam; Heimann, Heinrich; Damato, Bertil; Coupland, Sarah E.

doi:10.1111/pcmr.12767

Cited by 42 publications

(64 citation statements)

References 59 publications

(110 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Table 1 summarizes the reported number of cases for each mutation, the percentage of mutations detected as well as any associated clinicopathological features. 11,15,16,20,[22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] BRAF is a serine-threonine kinase responsible for activating the next kinase in the pathway, MEK. BRAF mutations have been found in 29.7% (n=167) of conjunctival melanomas (n=563) reported to date, both primary and metastatic (Table 1).…”

Section: Genetic and Epigenetic Changes In Conjunctival Melanomamentioning

confidence: 99%

“…These scores are based on evaluating the horizontal epithelial involvement, the vertical depth and the cellular atypia of the tumor cells. 10,11 Pre-existing PAM lesions give rise to 57% to 76% of conjunctival melanomas, 7,12 while 13% to 50% of them arise from PAM with severe atypia 8 (Figure 1). On the contrary, PAM without atypia, complexion associated/benign acquired melanosis have no established link with the development of conjunctival melanoma.…”

Section: Introductionmentioning

confidence: 99%

“…11,22,26,27,30,33,36,50 They are more common in younger male patients and are associated with an increased metastatic potential 30,33,50 via both the lymphatic and the vascular route. 11 Clinically, BRAF-mutant conjunctival melanomas arise more frequently on the bulbar than the palpebral conjunctiva, 30,33 which may also indicate the potential pathogenic role of exposure to UV radiation for the development of such tumors. Finally, they are associated with a greater depth of invasion.…”

mentioning

confidence: 99%

“…Finally, they are associated with a greater depth of invasion. 11,22 Following BRAF, the most common mutated gene in the MAPK pathway is NRAS. NRAS belongs to the RAS kinase family of small guanine nucleotide-binding proteins (HRAS, KRAS, NRAS) that become activated by receptor tyrosine kinases.…”

mentioning

confidence: 99%

“…NRAS belongs to the RAS kinase family of small guanine nucleotide-binding proteins (HRAS, KRAS, NRAS) that become activated by receptor tyrosine kinases. NRAS mutations are present in 6.4% (n=36) of conjunctival melanomas and up to 28% of cutaneous melanomas (Table 1) 11,16,20,26,27,35,37,39 and are not found in uveal melanomas. 49,52 In 88.9% (n = 32) of cases, NRAS mutations are located in codon 61, where a glutamine (Q) is substituted either by an arginine (R) in 40.6% (n=13) of them, by a lysine (K) in 15.6% (n=5) of them, by a histidine (H) in 9.4% (n=3) of them or by a leucine (L) in 9.4% (n=3) of them.…”

mentioning

confidence: 99%

See 4 more Smart Citations

<p>Conjunctival Melanoma: Update on Genetics, Epigenetics and Targeted Molecular and Immune-Based Therapies</p>

Gkiala¹,

Palioura²

2020

OPTH

View full text Add to dashboard Cite

Purpose: To present the molecular mechanisms involved in the pathogenesis of conjunctival melanoma (CM) and review the existing literature on targeted molecular inhibitors as well as immune checkpoint inhibitors for the management of locally advanced and metastatic disease. Methods: A comprehensive review of the literature was performed using the keywords "conjunctival melanoma", "immune checkpoint inhibitors", "BRAF inhibitors", "MEK inhibitors", "CTLA4 inhibitors", "PD1 inhibitors", "c-KIT mutations", "BRAF mutations", "NRAS mutations", "dabrafenib", "trametinib", "vemurafenib", "ipilimumab", "pembrolizumab", and "nivolumab". A total of 250 articles were reviewed and 120 were included in this report. Results: Mutations of mediators in the MAP kinase pathway, such as RAS, BRAF, MEK and ERK, and mutations of the PI3K/AKT/mTOR pathway play a major role in the pathogenesis of conjunctival melanoma. In addition, alterations of c-KIT, NF1, TERT, chemokine receptors as well as chromosomal copy number alterations and micro RNAs are thought to have a causative association with CM development. Targeted molecular inhibitors, such as BRAF and MEK inhibitors, are currently being implemented in the therapy of BRAF-mutated CM. Furthermore, immune checkpoint PD-1 and CTLA4 inhibitors with favorable clinical outcomes in the treatment of cutaneous melanoma have increased recurrence-free survival and reduced metastatic spread in CM cases. Conclusion: The complex molecular mechanisms that contribute to the development of CM can be targeted both by molecular inhibitors of oncogenic pathways as well as immune checkpoint inhibitors in order to halt progression of the disease and increase survival.

show abstract

Section: Genetic and Epigenetic Changes In Conjunctival Melanomamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

<p>Conjunctival Melanoma: Update on Genetics, Epigenetics and Targeted Molecular and Immune-Based Therapies</p>

Gkiala¹,

Palioura²

2020

OPTH

View full text Add to dashboard Cite

show abstract

Neoplasms of the Eye and Orbit

Alvarez¹,

Ponce²,

Chevez‐Barrios³

et al. 2022

Holland‐Frei Cancer Medicine

View full text Add to dashboard Cite

Overview Cancers of the eye and orbit are associated with diverse pathological conditions, disease prognosis, and significant mortality. The survival rates vary among patients from different countries and have been reported to be significantly lower in those from developing countries compared to those noted in the United States owing mainly to delay in diagnosis associated with advanced‐stage disease and unavailability of treatments. In this article, we provide an overview of the most common and rare ophthalmic malignancies that include ocular surface, external and adnexal diseases, and orbital and intraocular malignancies. We summarize the incidence, histopathology, risk factors, molecular alterations, clinical presentation, diagnostic evaluation, and therapeutic approaches for these diseases. We also describe the first‐line and salvage treatments and their complications. These treatments depend on disease stage at presentation and include pathology‐guided excision, Mohs microsurgery, chemo‐reduction, chemoprophylaxis, adjuvant chemotherapy after enucleation, and/or neoadjuvant chemotherapy. Complications include symblepharon, scarring, and limbal stem cell deficiency while incomplete excision of eyelid tumors may result in recurrence of larger and more aggressive tumors. Currently, identification of genetic abnormalities identified in genomic profiling of patient tumors improves treatment selection. Early diagnosis and involvement of an ocular oncologist at the time of diagnosis will optimize the therapeutic management of patients with these diseases.

show abstract

OSCAA: A two‐dimensional Gaussian mixture model for copy number variation association analysis

Yu,

Luo,

Cai

et al. 2024

Genetic Epidemiology

View full text Add to dashboard Cite

Copy number variants (CNVs) are prevalent in the human genome and are found to have a profound effect on genomic organization and human diseases. Discovering disease‐associated CNVs is critical for understanding the pathogenesis of diseases and aiding their diagnosis and treatment. However, traditional methods for assessing the association between CNVs and disease risks adopt a two‐stage strategy conducting quantitative CNV measurements first and then testing for association, which may lead to biased association estimation and low statistical power, serving as a major barrier in routine genome‐wide assessment of such variation. In this article, we developed One‐Stage CNV–disease Association Analysis (OSCAA), a flexible algorithm to discover disease‐associated CNVs for both quantitative and qualitative traits. OSCAA employs a two‐dimensional Gaussian mixture model that is built upon the PCs from copy number intensities, accounting for technical biases in CNV detection while simultaneously testing for their effect on outcome traits. In OSCAA, CNVs are identified and their associations with disease risk are evaluated simultaneously in a single step, taking into account the uncertainty of CNV identification in the statistical model. Our simulations demonstrated that OSCAA outperformed the existing one‐stage method and traditional two‐stage methods by yielding a more accurate estimate of the CNV–disease association, especially for short CNVs or CNVs with weak signals. In conclusion, OSCAA is a powerful and flexible approach for CNV association testing with high sensitivity and specificity, which can be easily applied to different traits and clinical risk predictions.

show abstract

Conjunctival melanoma copy number alterations and correlation with mutation status, tumor features, and clinical outcome

Cited by 42 publications

References 59 publications

<p>Conjunctival Melanoma: Update on Genetics, Epigenetics and Targeted Molecular and Immune-Based Therapies</p>

<p>Conjunctival Melanoma: Update on Genetics, Epigenetics and Targeted Molecular and Immune-Based Therapies</p>

Neoplasms of the Eye and Orbit

OSCAA: A two‐dimensional Gaussian mixture model for copy number variation association analysis

Contact Info

Product

Resources

About